Cancer Investigation, 31:516–521, 2013ISSN: 0735-7907 print / 1532-4192 onlineCopyright C© 2013 Informa Healthcare USA, Inc.DOI: 10.3109/07357907.2013.826239

IMAGING, DIAGNOSIS, PROGNOSIS

Soluble Interleukin-6 Receptor is a Prognostic Marker for Relapse-FreeSurvival in Estrogen Receptor-Positive Breast Cancer

Hye Sung Won,1 Young Ae Kim,2 Jun Sang Lee,3 Eun Kyoung Jeon,4 Ho Jung An,1 Der Sheng Sun,1

Yoon Ho Ko,1 and Jeong Soo Kim3

Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea,Uijeongbu-si, Gyeonggi-do, Korea,1 Clinical Research Laboratory, Uijeongbu St. Mary’s Hospital, College of Medicine, TheCatholic University of Korea, Uijeongbu-si, Gyeonggi-do, Korea,2 Department of Surgery, Uijeongbu St. Mary’s Hospital, Collegeof Medicine, The Catholic University of Korea, Uijeongbu-si, Gyeonggi-do, Korea,3 Department of Internal Medicine, Seoul St.Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu-si, Gyeonggi-do, Korea4

Considering the protumorigenic roles of interleukin-6 (IL-6)transsignaling, we assessed the serum levels of IL-6, solubleinterleukin-6 receptor (sIL-6R), and soluble glycoprotein 130(sgp130) in 143 patients with breast cancer. Serum levels of IL-6were elevated with advanced T and N stage. Serum levels ofsIL-6R were lower in patients with estrogen receptor-positivecancer. The median values of IL-6 and sgp130 did not differbetween patients with recurrence and those withoutrecurrence. However, higher serum levels of sIL-6R at diagnosiswere associated with significantly shorter relapse-free survivalin patients with estrogen receptor-positive breast cancer.

Keywords: Breast cancer, Interleukin-6, Soluble interleukin-6receptor, Prognosis

INTRODUCTION

Interleukin-6 (IL-6) is a multifunctional cytokine secreted bymany cells, including B cells, T cells, macrophages, mono-cytes, osteoblasts, fibroblasts, and endothelial cells (1). IL-6was originally identified as a B-cell stimulatory factor, how-ever, it is now known that IL-6 plays a wide range of biolog-ical roles in normal homeostasis and immune responses (2).Serum levels of IL-6 are tightly regulated and are low or un-detectable under normal physiological conditions. However,IL-6 is overexpressed in response to various stimuli, such asinjury, inflammation, and infection (2). Recently, the role ofIL-6 in cancer progression has also attracted attention. Sev-eral studies have suggested that tumor cells from prostate,breast, and colon cancer produce IL-6 and that this inter-leukin stimulates tumor cell proliferation, angiogenesis, andmetastasis, resulting in cancer progression via autocrine andparacrine mechanisms (1).

IL-6 induces signaling via a cell-surface heterodimeric re-ceptor complex composed of a ligand-binding IL-6 receptor

Correspondence to: Jeong Soo Kim, MD, PhD, Department of Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The CatholicUniversity of Korea, 271 Cheon bo-ro, Uijeongbu-si, Gyeonggi-do, Korea. e-mail: drbreast@catholic.ac.krReceived 14 May 2013; revised 28 June 2013; accepted 15 July 2013.

and a signal-transducing receptor subunit, the glycoprotein130 (gp130) (3). The IL-6 receptor occurs in two forms: amembrane-bound form (mIL-6R) and a soluble form (sIL-6R). The sIL-6R can bind to IL-6 in circulation with affinitycomparable to that of mIL-6R. The complex comprising IL-6and sIL-6R can bind to and activate gp130 on target cells thatdo not express mIL-6R (2). gp130 is expressed on almost allcells of the body, whereas mIL-6R is expressed in a limitednumber of cells, such as B cells, macrophages, and hepato-cytes. Activation of mIL-6R-deficient cells that are respon-sive to IL-6 by using sIL-6R produced by other cells is called“IL-6 trans-signaling” (2, 3). gp130 can also occur in a sol-uble form; however, in contrast with sIL-6R, soluble gp130(sgp130) prevents the binding of IL-6 to the receptor, i.e.,sgp130 is a potent endogenous antagonist of the IL-6/sIL-6R complex and selectively inhibits IL-6 trans-signaling (2).Consequently, the effect of IL-6 is regulated by soluble recep-tors, such as sIL-6R and sgp130, which enhance or inhibitIL-6 trans-signaling. The serum levels of sIL-6R and sgp130are relatively high compared with serum levels of IL-6. Thesehigh levels of sIL-6R and sgp130 seem to act as a buffer forIL-6 and they could be critical regulators of IL-6 activity bystabilizing IL-6 and enhancing IL-6-mediated signaling.

This study aimed to investigate the clinical significanceand prognostic role of IL-6 trans-signaling in breast cancerby measuring the serum levels of IL-6, sIL-6R, and sgp130.

MATERIALS AND METHODS

PatientsOne hundred fifty-six patients, who underwent curativesurgery for breast cancer at Uijeongbu St. Mary’s Hospital be-tween January 2004 and December 2007, were evaluated. Weexcluded patients who had received neoadjuvant chemother-apy. Patients with incomplete data or those who were lost

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to follow-up were also excluded. Finally, 143 patients wereincluded in this study. Clinical records and pathology re-ports were reviewed, retrospectively. The following clinicaldata were collected: age, sex, clinical and pathological stag-ing, estrogen receptor (ER), progesterone receptor (PR), andhuman epidermal growth factor receptor 2 (HER2) status,surgery type, adjuvant chemotherapy, radiotherapy, hormonetherapy, recurrence, and survival. Approval of the ethics com-mittee of the Institutional Review Board of The Catholic Uni-versity of Korea, Uijeongbu St. Mary’s Hospital, was obtained.Informed consent was provided according to the Declarationof Helsinki.

Serum sampling and determination of IL-6, sIL-6R,and sgp130 concentrationsVenous blood samples were taken from patients at the time ofdiagnosis (before surgery) and centrifuged at 3,000 rpm for10 min. The serum obtained was divided into aliquots andstored at −20◦C until assayed for cytokines. The serum con-centrations of IL-6, sIL-6R, and sgp130 were determined us-ing a commercially available enzyme-linked immunosorbentassay kit in accordance with the manufacturer’s instructions(Quantikine, R&D Systems, Minneapolis, MN, USA). Thisassay uses the quantitative sandwich enzyme immunoassaytechnique, and can detect both the free and bound fractionsof IL-6, sIL-6R, and sgp130. The minimum detectable lev-els of IL-6, sIL-6R, and sgp130 were typically 0.7 pg/mL, 6.5pg/mL, and 0.05 ng/mL, respectively.

Immunohistochemical stainingER and PR were considered positive when more than 10%of the tumor cells showed a distinct nuclear staining. Theimmunohistochemical staining of HER2 was classified as 0,1+, 2+, or 3+ according to membranous staining intensity.HER2 status was defined as positive in the presence of ahigh degree of expression (3+), assessed by immunohisto-chemistry, or 2+ immunoreactions with gene amplificationdetected by fluorescence in situ hybridization according tocriteria described elsewhere. p53 staining was consideredpositive when more than 10% of the cell nuclei were stained.

Statistical analysisContinuous variables, including serum cytokine levels, wereexpressed as median, minimum, and maximum values, be-cause these variables were not normally distributed. Com-parisons of continuous variables were made using theMann–Whitney U test and the Kruskal–Wallis test. The chi-square test and Fisher’s exact test were used for comparisonsof categorical variables. To determine the significance andstrength of bivariate associations, we used Spearman’s rankcorrelation coefficient. Relapse-free survival (RFS) was de-fined as the time from surgery to disease recurrence. Univari-ate survival analysis was performed using the Kaplan–Meiermethod, and the log-rank test was applied to assess statisticaldifferences. Multivariate survival analysis was performed us-ing the Cox hazards regression model. All statistical analyses

Table 1. Clinicopathological Characteristics of the Patients withBreast Cancer

All patients All patients(n = 143) (n = 143)

Characteristics No. (%) Characteristics No. (%)

Age (years) ERMean±SD 50.4 ± 11.9 Positive 93 (65.0)

Sex Negative 50 (35.0)Men 2 (1.4) PRWomen 141 (98.6) Positive 89 (62.2)

Tumor size Negative 54 (37.8)≤2cm 57 (39.9) HER2>2cm, ≤ 5cm 73 (51.0) Positive 21 (15.3)>5cm 13 (9.1) Negative 116 (84.7)

No. of positiveaxillary LN Surgery0 84 (58.7) BCS 70 (49.0)1–3 30 (21.0) MRM 73 (51.0)4–9 19 (13.3) Adjuvant RT 95 (66.4)≥ 10 10 (7.0) Adjuvant CTx

LNR CMF 88 (64.2)Mean±SD 0.152 ± 0.270 A 2 (1.5)

Grade AT 47 (34.3)Well 27 (18.9) Adjuvant HTxModerate 56 (39.2) Tamoxifen 83 (81.4)Poor 60 (41.9) AI 19 (18.6)

Note: LN, lymph node; LNR, lymph node ratio; ER, estrogen receptor; PR,progesterone receptor; HER2, human epidermal growth factor receptor 2; BCS,breast conserving surgery; MRM, modified radical mastectomy; RT, radiother-apy; CTx, chemotherapy; CMF, cyclophosphamide, methotrexate, 5-fluorouracil; A,anthracycline-containing regimen; AT, anthracycline and taxane regimen; HTx, hor-mone therapy; AI, aromatase inhibitor.

were performed using the SPSS program (version 18.0) andp < .05 was considered statistically significant.

RESULTS

Patient characteristicsThe clinicopathological characteristics of the 143 patients aresummarized in Table 1. The mean age of the patients was 50.4(range, 26–89) years. Two men with breast cancer were in-cluded. The most common histological subtype was invasiveductal carcinoma (138; 96.5%). In addition, invasive lobularcarcinoma, mucinous carcinoma, and medullary carcinomawere observed in three (2.1%), one (0.7%), and one (0.7%)patients, respectively. Of 143 patients, ER-positive patientswere 93 (65.0%) and HER2-positive patients were 21 (15.3%).

Serum levels of IL-6, sIL-6, and sgp130 and correlationanalysesThe median values of IL-6, sIL-6, and sgp130 according toclinicopathological variables are presented in Table 2. The IL-6 values were significantly elevated with the increasing num-ber of positive axillary lymph nodes (p = .045). sIL-6R lev-els were higher in patients with ER-negative tumors than inpatients with ER-positive tumors (p = .036). There was nodifference in the levels of sgp130 according to clinicopatho-logical variables.

We analyzed the relationship between the serum levels ofIL-6, sIL-6R, and sgp130. The levels of IL-6 were positivelycorrelated with the levels of sgp130 (R2 = 0.168; p = .045).

Copyright C© 2013 Informa Healthcare USA, Inc.

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Table 2. Serum Levels of IL-6, sIL-6R, and sgp130 Stratified byClinicopathological Variables

IL-6 sIL-6R sgp130(pg/mL) (pg/mL) (ng/mL)

Variables Median P Median P Median p

Tumor size .188 .388 .119≤2cm 1.05 32438.15 156.83>2cm, ≤5cm 1.59 31725.55 163.97>5cm 3.02 33069.48 146.90

No. positive .045 .557 .148axillary LN0 1.11 31642.84 161.431–3 1.54 32043.27 154.744–9 1.90 35303.90 157.74≥10 2.93 32042.53 179.40

ER .640 .036 .176Positive 1.34 31090.19 161.78Negative 1.36 33346.32 158.04

PR .324 .224 .288Positive 1.15 31467.93 157.60Negative 1.97 32167.93 163.79

HER2 .507 .761 .390Positive 1.52 32960.89 156.83Negative 1.20 32069.44 159.74

p53 .131 .843 .221Positive 1.17 32469.74 165.45Negative 1.63 32012.44 158.01

Note: LN, lymph node; ER, estrogen receptor; PR, progesterone receptor; HER2, hu-man epidermal growth factor receptor 2. Significant values are bold.

There were no significant correlations between the levels ofsIL-6R and IL-6 or those of sIL-6R and sgp130.

Survival outcomeTwenty-four (16.8%) of the 143 patients with breast cancerdeveloped recurrence at a median of 31.3 months (range,6.5–65.0 months). Four patients exhibited local recurrence,19 patients exhibited distant metastases, and one patient ex-hibited both local recurrence and distant metastases. Themost common sites of distant metastases were the bone(27%), liver (27%), and lung (21%).

Advanced T and N stage were higher in patients withrecurrence than in patients without recurrence (p = .004and .001, respectively). Accordingly, the percentage of pa-tients who received modified radical mastectomy and taxane-containing adjuvant chemotherapy was higher in the groupwith recurrence than in the group without recurrence (p =.001 and .003, respectively). There were no significant differ-ences in grade, expression of ER, PR, and HER2, adjuvant ra-diotherapy, or hormone therapy between the recurrent andnonrecurrent groups (Table 3).

The mean levels of IL-6 and sgp130 did not differ signif-icantly between patients with recurrence and without recur-rence. There was a trend for higher sIL-6R levels in patientswith recurrence compared with those without recurrence(p = .097). The ratios of sIL-6R to sgp130, sIL-6R to IL-6,and sgp130 to IL-6 were calculated; there were no differencesin these ratios according to the recurrence (Table 4).

Univariate analysis showed that T stage and N stage werethe prognostic factors that significantly affected 3-year RFS

Table 3. Clinicopathological Characteristics of the Patients Accordingto Recurrence

Non-recurrent RecurrentGroups (n = 119) Groups (n = 24)

Characteristics No. (%) No. (%) P

Age (years) .829Mean ± SD 50.5 ± 11.7 49.92 ± 12.9

Sex .206Men 1 (0.8) 1 (4.2)Women 118 (99.2) 23 (95.8)

Tumor size .004≤2cm 54 (45.5) 3 (12.5)>2cm, ≤5cm 57 (47.9) 16 (66.7)>5cm 8 (6.7) 5 (20.8)

No. of positive axillary LN .0010 77 (64.7) 7 (29.2)1–3 25 (21.0) 5 (20.8)4–9 11 (9.2) 8 (33.3)≥10 6 (5.0) 4 (16.7)

LNR .002Mean±SD 0.112 ± 0.238 0.350 ± 0.330

Grade .387Well 24 (20.2) 3 (12.5)Moderate 48 (40.3) 8 (33.3)Poor 47 (39.5) 13 (54.2)

ER .775Positive 78 (65.5) 15 (62.5)Negative 41 (34.5) 9 (37.5)

PR .371Positive 76 (63.9) 13 (54.2)Negative 43 (36.1) 11 (45.8)

HER2 .401Positive 16 (14.2) 5 (20.8)Negative 97 (85.8) 19 (79.2)

Surgery .001BCS 67 (56.3) 3 (12.5)MRM 52 (43.7) 21 (87.5)

Adjuvant RT 83 (70.3) 12 (50.0) .054Adjuvant CTx .003

CMF 81 (69.8) 7 (33.3)A 2 (1.7) 0AT 33 (28.4) 14 (66.7)

Adjuvant HTx .065Tamoxifen 70 (78.7) 13 (100.0)AI 19 (21.3) 0

Note: LN, lymph node; LNR, lymph node ratio; ER, estrogen receptor; PR,progesterone receptor; HER2, human epidermal growth factor receptor 2; BCS,breast conserving surgery; MRM, modified radical mastectomy; RT, radiother-apy; CTx, chemotherapy; CMF, cyclophosphamide, methotrexate, 5-fluorouracil; A,anthracycline-containing regimen; AT, anthracycline and taxane regimen; HTx, hor-mone therapy; AI, aromatase inhibitor. Significant values are bold.

(Table 5). A larger tumor size and a higher number of ax-illary lymph node metastases were significantly correlatedwith a shorter RFS. Serum levels of IL-6, sIL-6R, and sgp130were divided into high or low levels using the median valueas cut-off point. There was a trend for a shorter RFS in pa-tients with high levels of serum sIL-6R at diagnosis; how-ever, this difference was not statistically significant (p = .098)(Figure 1A). We analyzed the RFS according to serum lev-els of sIL-6R stratified by ER status. There was no significantdifference in RFS according to serum levels of sIL-6R in pa-tients with ER-negative breast cancer, but high levels of serumsIL-6R at diagnosis were associated with significantly shorterRFS in patients with ER-positive breast cancer (p = .043)

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Table 4. Serum Levels of IL-6, sIL-6R, and sgp130 According to Recurrence

All Patients (n = 143) Non-recurrent Group (n = 119) Recurrent Group (n = 24)Cytokines Median (min–max) Median (min–max) Median (min–max) p

IL-6 (pg/mL) 1.34 (0–50.20) 1.34 (0–50.20) 1.81 (0–37.71) .880sIL-6R (pg/mL) 32039.35 (16579.74–59970.53) 31560.13 (16579.74–59970.53) 33471.77 (17441.80–53221.13) .097sgp130 (ng/mL) 159.37 (120.23–296.37) 159.37 (120.23–296.37) 160.94 (133.08–210.73) .812sIL-6R/sgp130 189.55 (92.49–399.93) 185.62 (92.49–375.44) 210.83 (106.67–399.93) .254sIL-6R/IL-6 21987.30 (454.94–588237.49) 23801.91 (454.94–588237.49) 14223.18 (943.54–166185.62) .233sgp130/IL-6 110.99 (3.34–4142.04) 117.77 (3.34–4142.04) 77.43 (4.22–457.36) .238

(Figure 1B). RFS did not differ according to serum levels ofIL-6 and sgp130 at diagnosis. In multivariate Cox regressionanalysis with sIL-6R, tumor size and number of metastaticaxillary lymph nodes, presence of more than four axillarylymph node metastases had only significant impact on RFSin breast cancer (hazard ratio = 4.795; 95% confidence inter-val 1.308, 17.578; p = .028).

DISCUSSION

IL-6 signaling is classified into two forms: (a) classic signalingvia the cell-surface mIL-6R/gp130 in complex with IL-6 and(b) trans-signaling via the IL-6/sIL-6R complex from the cir-culation combined with cells expressing gp130 (2). IL-6 ex-

Table 5. Univariate Survival Analysis According toClinicopathological Variables

Variables 3-year RFS (%) p

Tumor size≤2cm 96.5 .002>2cm, ≤5cm 87.7>5cm 76.9

No. of positive axillary LN0 96.4 .0011–3 90.04–9 78.9≥10 60.0

Histological gradeWell 96.3 .314Moderate 92.9Poor 85.0

HR statusPositive 90.9 .845Negative 87.9

HER2 statusPositive 81.0 .366Negative 91.4

p53Positive 93.6 .922Negative 88.5

IL-6Below the median 91.5 .576Above the median 88.9

sIL-6RBelow the median 93.0 .098Above the median 87.5

sgp130Below the median 87.5 .860Above the median 91.5

Note: LN, lymph node; HR, hormone receptor; HER2, human epidermal growth fac-tor receptor 2; RFS, relapse-free survival. Significant values are bold.

erts multiple effects on various target cells and organs via IL-6 trans-signaling. It has been shown that various target cells,such as hematopoietic progenitor cells, embryonic stem cells,many neural cells, and endothelial cells, are only responsiveto IL-6 through trans-signaling; hence, IL-6 trans-signalingis considered important (1–3).

IL-6 signaling plays important roles in immune response,hematopoiesis, the acute phase response, inflammation, andbone metabolism. During the past few years, many stud-ies have also provided strong evidence that the regulatorymechanism between IL-6, sIL-6R, and sgp130 is impairedin patients with cancer and that activation of IL-6 sig-naling is closely connected to cancer development (1, 3,4). Some tumor cells produce IL-6 and express the func-tional IL-6 receptor complex, which allows them to respondto IL-6 stimulation in an autocrine manner. Other tumorcells do not produce IL-6, but respond to IL-6 producedin the tumor microenvironment in a paracrine manner (1).Tumor-infiltrating immune cells such as neutrophils andmacrophages are an important source of IL-6, and they havebeen reported to contribute to tumor progression and inva-sion (1). IL-6 has a direct growth stimulatory effect on manytumor cells via the activation of signaling pathways, such asRas/Raf/MEK/Erk1/2, and increases the expression of severalsurvival proteins, such as Bcl-2 and survivin, resulting in tu-mor cell proliferation (1, 5). Recently, Lesina et al. reportedthat IL-6 trans-signaling is required for Kras-induced pan-creatic oncogenesis (4). IL-6 interacts with several pathwaysthat have protumorigenic activity, including cyclooxygenase-2, Wnt, the transforming growth factor-β , and the receptoractivator of nuclear factor kappa B (1). IL-6 signaling alsoplays an important role in promoting metastasis to organs,angiogenesis, and vascular remodeling (6). Therefore, IL-6signaling contributes comprehensively to tumorigenesis.

However, the majority of these studies were conducted invitro and there were few in vivo studies. In vivo studies, ithas been reported that the serum levels of IL-6 and sIL-6Rare elevated in some cancers and are associated with a poorclinical outcome (7–9). The circulating levels of IL-6 and sIL-6R were elevated in patients with multiple myeloma, coloncancer, and hepatocellular carcinoma compared with those ofthe healthy control group (10–12). An increased serum levelof IL-6 has been reported as being a predictive and/or prog-nostic marker in patients with recurrent or metastatic breastcancer (13, 14). Zhang et al. reported that among 46 patientswith metastatic breast cancer, patients who were unrespon-sive to chemoendocrine therapy showed significantly higher

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Figure 1. Kaplan–Meier survival curves for relapse-free survival according to serum levels of sIL-6R. (A) All patients with breast cancer (n = 143)(B) ER-positive breast cancer patients (n = 93).

serum IL-6 levels than did those who responded to chemoen-docrine therapy (14). Kovacs investigated the serum levelsof IL-6, sIL-6R, and sgp130 in patients with different typesof cancer, including 26 breast cancer cases (15). The resultsof that research showed that the serum levels of sIL-6R andsgp130 were elevated in some patients with cancer comparedwith controls, and it suggested that it might be necessary toassess related proteins, such as sIL-6R and sgp130, simultane-ously when evaluating IL-6. Becker et al. reported that block-ing sIL-6R during colitis-associated colon cancer suppressedcancer growth in vivo, suggesting that the soluble, rather thanthe membrane-bound, IL-6R controls tumor growth duringcolitis-associated colon cancer (16).

We measured the serum levels of these three parameterssimultaneously in 143 patients with breast cancer; by con-trast, previous studies assessed mainly IL-6 expression alone.The serum levels of IL-6 were significantly elevated withthe increasing number of positive axillary lymph nodes, andlarger tumor exhibited a trend for higher serum levels of IL-6. These results suggest that the serum levels of IL-6 at di-agnosis reflect tumor burden or advancement of the disease.Meanwhile, there were no significant differences in the serumlevels of IL-6 and sgp130 between patients with recurrenceand without recurrence. However, although this result wasnot statistically significant, patients with sIL-6R above themedian had shorter RFS compared with those with sIL-6Rbelow the median. In subgroup analysis based on ER status,this trend was statistically significant in ER-positive breastcancer but not in ER-negative breast cancer patients. On theother hand, median serum levels of sIL-6R were significantlylower in patients with ER-positive breast cancer than in pa-tients with ER-negative breast cancer. There appears to beno previous study about relationship between ER-positivityand serum levels of sIL-6R in breast cancer. However, somestudies in the area of endocrinology have shown relationshipsbetween menopause and alterations of the IL-6 related im-mune system (17–19). According to these studies, estrogendeficiency after menopause results in an increase of proin-flammatory cytokines such as interleukin-1, IL-6, and tumornecrosis factor alpha. Also, serum levels of sIL-6R increaseprogressively after ovariectomy, and hormone replacement

therapy suppresses serum levels of sIL-6R (18, 19). These re-sults indicate that sIL-6R is under the direct inhibitory con-trol of estrogen. Other studies reported that glucocorticoidsinhibit estrogenic activity and enhance generation of sIL-6R of lymphoid cells or some cancer cells (20, 21). Theserelationships support the possibility that IL-6/ sIL-6R mayplay a role in ER positive breast cancer. According to our re-sults, inhibitory effect of estrogen on sIL-6R was more promi-nent in patients with ER-positive breast cancer, and higherserum levels of sIL-6R were associated with poor prognosisin ER-positive breast cancer. However, in multivariate anal-ysis, lymph node metastasis was only strong prognostic fac-tor for RFS. Therefore, large-scale additional studies aimed atevaluating the definitive role of sIL-6R in ER-positive breastcancer are needed.

In summary, IL-6 transsignaling has emerged as a con-tributor to the tumor microenvironment and protumorigenicactivity. We found that initial serum IL-6 levels were asso-ciated with T and N stages in breast cancer, and that initialserum sIL-6R levels are a potential prognostic marker of re-currence in patients with ER-positive breast cancer. Furtherstudies are needed to identify more clearly the role of sIL-6Rin ER-positive breast cancer and to validate therapeutic ap-proaches that target IL-6 trans-signaling in breast cancer.

DECLARATION OF INTEREST

The authors report no conflicts of interest. The authors aloneare responsible for the content and writing of the paper.

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